The proposed studies will investigate the neural substrates mediating susceptibility to depression in a genetic rat model. Our recent work with the congenitally helpless rat has revealed a pattern of metabolic abnormality in prefrontal cortex (PFC) and anterior cingulate cortex (ACg) that strongly parallels PET and fMRI findings from depressed humans. These rats also appear to have another, much larger, abnormality localized to the paraventricular hypothalamic nucleus (PVH). Based on these results, we seek to further investigate the role of brain regions related to the hypothalamic-pituitary-adrenal axis in congenitally helpless rats. Four specific aims are proposed: 1) Extend metabolic mapping of the congenitally helpless rat brain to regions that provide regulatory input to the PVH (hippocampus, septal area, bed nucleus of the stria terminalis), regions related to monoaminergic function (ventral tegmental area, raphe nuclei, habenula), and other regions implicated in emotional behavior (amygdala, basal ganglia, periacqueductal gray). 2) Test the hypothesis that the PVH metabolic abnormality is related to increased production of corticotropin-releasing hormone (CRH) by performing in situ hybridization for CRH mRNA. 3) Test the hypothesis that elevated CRH secretion will cause metabolic abnormalities in PFC, ACg, and other regions similar to those identified in the congenitally helpless rat by chronically administering CRH to normal rats, followed by metabolic brain mapping. 4) Identify brain regions linked to depression remission by administering an antidepressant (fluoxetine) to congenitally helpless rats and determining its effect on regional brain metabolism, CRH mRNA, and behavioral outcome measures. The collective results should help to integrate the roles of the hypothalamus, frontal cortex, and serotonin system in depression and its treatment.